Canonical and non-canonical functions of the non-coding RNA component (TERC) of telomerase complex

Abstract

The telomerase complex consists of a protein component (TERT), which has reverse transcriptase activity, and an RNA component (TERC), which serves as a template for telomere synthesis. Evidence is rapidly accumulating regarding the non-canonical functions of these components in both normal or diseased cells. An oligonucleotide-based drug, the first telomerase inhibitor, secured FDA approval in June 2024. We recently summarized the non-canonical functions of TERT in viral infections and cancer. In this review, we expand on these non-canonical functions of TERC beyond telomere maintenance. Specifically, we explore TERC's roles in cellular aging and senescence, immune regulation, genetic diseases, human cancer, as well as involvement in viral infections and host interactions. Finally, we discuss a transcription product of telomere repeats, TERRA, and explore strategies for targeting TERC as a therapeutic approach.

Keywords: Non-canonical functions; Non-coding RNAs; TERC; TERT; Telomerase; Telomeres.

Fig. 1

Canonical functions of TERT and TERC. Schematic illustration of the TERC structure and its role in the human telomerase ribonucleoprotein complex, which includes TERT, NOP10, dyskerin, GAR1, NHP2, and TCAB1. TERC provides the template (3’-CAAUCCCAAUC-5’) for hTERT to extend the telomere by adding TTAGGG DNA repeats. The H/ACA box recruits two sets of H/ACA-box-binding proteins, including NOP10, dyskerin, GAR1, and NHP2. TCAB1 is recruited through its binding with TERC and the H/ACA-box-binding proteins

Fig. 2

Non-canonical functions of TERC. (a) Biological processes that can be regulated by TERC according to current research. (b) Schematic illustration of potential mechanisms by which TERC performs known and unknown non-canonical functions